JPH09124583A - Alkenylbenzoylguanidine derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject new compound of a medicine suppressing cellular Na+/H- countertransporting body, expressed by a specific formula, especially suitable for the treatment of arrhythmia, manifesting a good cardio-protective effect, and especially suitable for the prevention and treatment of infarct diseases.

SOLUTION: This alkenyl-benzoylguanidine derivative is an objective compound of formula I [R¹, R² are each H, a halogen, a 1-6C alkyl, CN, NO₂, CF₂, CH₂F, CHF₂, etc.; R³ is-CR⁵=CR⁶R⁷, -C(R⁶R⁵)-CR⁷= CR⁹R⁸, etc., a 3-7C cycloalkenyl or a 4-8C cyloalkenylalkyl; R⁵ to R⁹ are each H or a 1-6C alkyl], e.g. N-diaminomethylene-2-methyl-4-(1-cyclopenten-3-yl)-5-methylsulfonylbenzamide. Further, in order to obtain the compound, it is preferable to react, etc., a compound of formula II (Q is an easily nucleophilically substitutable leaving group such as Cl or Br) with guanidine.

COPYRIGHT: (C)1997,JPO

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to novel alkenyl-benzoylguanidine derivatives and physiologically acceptable salts thereof, a process for producing them, and pharmaceutical preparations containing them, especially for arrhythmia, angina and infarction. The present invention relates to a pharmaceutical preparation useful for therapeutic or prophylactic treatment and a method for producing the medicine.

[0002]

BACKGROUND OF THE INVENTION The most well known active compound of the acylguanidine group is amiloride. However, this substance exhibits primarily hypotensive and salinizing effects, which are not desirable, especially when treating heart rhythm disorders, while its antiarrhythmic effect is only very weak. Furthermore, structurally similar compounds are known, for example from EP 04 16 499.

[0003]

The object of the present invention is to provide novel compounds having useful properties, in particular novel compounds which can be used in the manufacture of a medicament. The subject of the present invention is also a good cardioprotective effect and is therefore suitable for the treatment of infarction, for the prevention of infarction and also for the treatment of angina, and also for all types of etiological hypoxic disorders and An object of the present invention is to provide a pharmaceutical agent which can counter an ischemic disorder and treat a disorder caused primarily or secondaryly by such a disorder, and which is also suitable for prevention. A further object of the present invention is the development of diseases resulting from cell proliferation, such as arteriosclerosis, late complications of diabetes, tumor diseases, fibrotic diseases, especially lung, liver and kidney fibrosis, and also organ hypertrophy and hyperplasia. And in addition to this, in the diagnosis of diseases associated with increased activity of Na ⁺ / H ⁺ antiporters such as those in erythrocytes, platelets or leukocytes,
It is to provide a medicine suitable for use in diagnostic tests. A further object of the present invention is to provide an intermediate for producing another pharmaceutically active compound.

[0004]

It has been found that the novel alkenyl-benzoylguanidine derivatives of the formula I and the physiologically acceptable salts thereof according to the invention solve the above-mentioned problems. Novel alkenyl according to the invention
Benzoylguanidine derivatives and their physiologically acceptable salts are represented by formula I below:

Embedded image

[0005] In the formula, R ¹ and R ² are each independently H,
Hal, A, CN, NO ₂ , CF ₃ , CH ₂ F, CHF ₂ ,
A _{C 2 F 5, CH 2 CF} 3 or SO _n -R ^4, R ³ is
^{-CR 5 = CR 6 R 7,} -C (R 6 R 5) -CR 7 = CR 9 R 8
Or ^{-C (R 6 R 5) -C} (R 7 R 8) -CR 9 = CR 10
R ¹¹ or cycloalkenyl having 3 to 7 C atoms or cycloalkenylalkyl having 4 to 8 C atoms, R ⁴ is A or Ph,
R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ are each independently H or A, and A is a C atom 1
Is an alkyl having ~ 6 and Hal is F, Cl,
Br or I, Ph is phenyl, which is unsubstituted or has one, two or three substituents A, OA, NR ⁴ R ⁵ , F, Cl, Br, Has I or CF ₃ , and n is 1 or 2.

It has been found that the compounds of formula I and their physiologically tolerable salts possess valuable pharmacological properties, combined with good tolerability. These novel compounds are inhibitors of cellular Na ⁺ / H ⁺ antiporters. That is, Na ⁺ / H ⁺ exchange mechanism (Duesing et al., Med. Klin., 87 , 378−
384 (1992)) and is therefore a good antiarrhythmic drug and is particularly suitable for the treatment of arrhythmias that develop as a result of lack of oxygen.

The novel substances according to the invention show a good cardioprotective effect and are therefore suitable for the treatment of infarction, the prevention of infarction and also the treatment of angina. Furthermore, these substances are capable of combating all types of etiological hypoxic and ischemic disorders and treating the disorders caused primarily or secondary by such disorders. These active compounds are also particularly suitable for prophylaxis. Having a prophylactic effect in etiological hypoxia or ischemia, these compounds also protect the organs transiently supplied in surgery, protect organs removed in organ transplantation, and angiogenic. It can also be used in cardiac surgery, in ischemia of the nervous system, in the treatment of shock conditions and also in the prophylactic prevention of essential hypertension.

[0008] Furthermore, these compounds are used for diseases caused by cell proliferation, such as arteriosclerosis, late complications of diabetes, tumor diseases, fibrotic diseases, especially lung, liver and kidney fibrosis, and also organs. It can also be used as a therapeutic agent in hypertrophy and hyperplasia. In addition to this,
It is also suitable for use in diagnostic tests in the detection of diseases associated with increased activity of Na ⁺ / H ⁺ antiporters such as erythrocytes, platelets or leukocytes. The effect of the compounds according to the invention can be determined by methods known per se, for example by N. Escobales and J. Figueroa, J. Memb.
rane Biol., 120, 41-49 (1991) or L. Counillo.
Mol.Ph by n, W. Scholz, HJ Lang and J. Pouyssegur
armacol., 44, 1041-1045 (1993). Examples of suitable laboratory animals are mice, rats, guinea pigs, dogs, cats, monkeys or pigs.

The compounds according to the invention can therefore be used as pharmaceutically active ingredients in human and veterinary medicine. Furthermore, these compounds can also be used as intermediates for preparing other pharmaceutically active ingredients. In the above formula, A is a branched or unbranched alkyl group having 1 to 6, preferably 1 to 4, especially 1, 2 or 3, C atoms, particularly preferably methyl. And still more preferably ethyl, propyl, isopropyl, butyl or isobutyl, even more preferably sec-butyl, tert-butyl, pentyl, isopentyl (3-methylbutyl), hexyl or isohexyl (4-methylpentyl). is there.

R ¹ is preferably H, A or Hal,
Particularly Br or Cl. R ¹ is particularly preferably methyl or ethyl. However, R ¹ is also preferably CH ₂ F, CHF ₂ , CF ₃ or C ₂ F ₅ . R ¹ is preferably ortho-to the guanidine group.
Exists in position. R ² is preferably A-SO ₂ , C
F ₃ , Cl, Br or NO ₂ . R ² is particularly preferably H ₃ C—SO ₂ —. The group R ² is preferably located in the 3- or 5-position relative to the benzoylguanidine group. R ³ is preferably, -CR ⁵ = CR ⁷ R ⁶ or -
C (R ⁶ R ⁵⁾ a -CR ⁷ = CR ⁹ R ^8.

R ³ is also preferably cyclopropenyl, cyclobutenyl, 3-cyclopentyl, 4-cyclopentenyl, 3- or 4-cyclohexenyl, 3
-, 4- or 5-cycloheptenyl or the corresponding cycloalkenylmethyl derivatives. R ⁴ is preferably methyl, ethyl or phenyl. Ph is preferably unsubstituted or substituted with one Cl, B
Phenyl with r, A, OA, NH ₂ , NHA, NA ₂ or CF ₃ . R ^{5 to} R ¹¹ are each, independently of one another, H and / or A, in particular hydrogen and / or methyl. Hal is preferably
F, Cl or Br.

Generally, there are several groups present, for example R ^5-
All groups such as R ¹¹ can be the same or different. That is, they are independent of each other. The compounds according to the invention can be in the form of cis / trans isomers. The present invention includes both the pure cis and trans forms of these compounds as well as mixtures. These compounds can also exist in racemic forms, which can be resolved into enantiomers.

Accordingly, the present invention is particularly directed to formula I
At least one of said groups present in the molecule of
It relates to compounds having one of the suitable meanings. These compounds
Several suitable groups of products are represented by formulas Ia-Ih below.
These Formulas Ia-Ih correspond to Formula I and are described in detail below.
The radicals not mentioned have the meanings given above for the case of the formula I.
With: In Ia, R¹Is A, and R^TwoIs
-SO _Two-A, NO_TwoOr CF_ThreeIs; Ib smell
And R¹Is H or Hal, and R^TwoIs -SO_Two
A, NO_TwoOr CF_ThreeRc in Ic¹Is A
Or H and R^TwoIs -SO_TwoA and R^ThreeIs
-CR^Five= CR⁶R⁷Where R^Five~ R⁷Are each
Independently of one another, is H or methyl;

In Id, R ¹ is A or H,
R ² is -SO ₂ -A, and R ³ is -C (R ⁵ R ⁶⁾
A -CR ⁷ = CR ⁸ R ^9, wherein R ⁵ to R ⁹ are each, independently of one another, are H or methyl; in Ie, R ¹ is A or H, R ² is -SO ₂ is -A, and R ³ is ^{-C (R 5 R 6) -CR} 7 R 8 -CR 9 = C
R ¹⁰ R ¹¹ wherein R ^{5 to} R ¹¹ are each, independently of one another, H or methyl; in If, R ¹ is H or A and is in the ortho-position to the benzoylguanidine group. And R ² is —SO ₂ —A
And meta-to the benzoylguanidine group
In the position; in Ig, R ³ is cycloalkenyl having 3 to 7 C atoms, and is in the para-position to the amido group, and R ² is —SO ₂ —A, And in the meta-position with respect to the amide group;
In Ih, R ¹ is A or H and R ² is —SO ₂
Is -A, R ³ is cycloalkenyl having 3-7 C atoms, and R ³ is para to the benzoylguanidine group - present in the position.

The present invention also relates to a process for the preparation of compounds of formula I and salts thereof according to claim 1, which process comprises the formula II:

Embedded image Wherein R ¹ , R ² and R ³ have the meanings given above and Q is Cl, Br, OA, O-CO-A, O-CO-P.
h or OH, or another reactively esterified OH group, or Q is a leaving group that can be easily nucleophilically substituted. React with guanidine, or

Formula III:

[Chemical 6] Wherein R ¹ and R ² have the meanings given above, and L is
F, Cl, Br or I, represented by benzoylguanidine compound in, if the transition metal catalyst and optionally, in the presence of an activating agent, wherein IV: in R ³ -H IV formula, R ³ is Reacting with an unsaturated hydrocarbon compound having the above meaning, or

Corresponding to formula I, but instead of its one or more hydrogen atoms, one or more reducible groups such as alkynyl groups, and / or one or more Additional C-C bond and / or C-N
A compound having a bond is treated with a reducing agent, or a compound corresponding to formula I, but having one or more solvolytic groups in place of one or more hydrogen atoms thereof, Treatment with a solvolysis agent, or isomerization of the group R ³ , or a transition metal catalyst and / or
By rearrangement of the double bond under the action of a metal carbonyl, it is converted to another group R ³ and / or the resulting base of formula I is converted to one of its salts by treatment with an acid. The method is characterized in that

The compounds of formula I can also be found in publications (for example Methoden der Organisch by Houben-Weyl).
en Chemie [Method of Organic Chemistry], Georg-Thieme Publisher,
Stuttgart ； Organic Reactions, John Wiley & Sons, In
c., New York, and methods known per se, such as those described in the above-mentioned patent applications), particularly suitable for the reaction,
It is produced under known reaction conditions. Use can also be made of variants which are known per se, but are not mentioned here in greater detail. If desired, the starting materials can also be generated in situ by such a method that they are further reacted immediately without isolation from the reaction mixture to give the compounds of the formula I.

Preferably, the compound of formula I is
An activated carboxylic acid derivative of formula II, wherein Q is particularly preferably Cl or -O-CH
₃ ) is reacted with guanidine. In this reaction, the free carboxylic acid compound II (Q
OH) is converted in a manner known per se to convert it into a specific active derivative, which derivative is then directly reacted with guanidine without isolation of the intermediate. . Examples of methods that do not require intermediate isolation include activation methods using carbonyldiimidazole or dicyclohexylcarbodiimide, or modified Mukayama (Angew. Chem., 91 , 788-812 (1979).
).

The carboxylic acid compounds and carboxylic acid derivatives of the formula II are generally known. These compounds are especially suitable for the Heck reaction [J. Org. Chem. 46 , 10
67 (1981)] or by a Pd-catalyzed cross-coupling reaction. Preferred catalysts are, for example, Pd (PPh ₃ ) ₄ , (Ph ₃ P) ₂ PdCl ₂ , Pd
(CH ₃ COO) ₂ or Pd- (II) - [1,1'-
Bis (diphenylphosphine) ferrocene] chloride, preferably with CuI present.

The carboxylic acid compounds of formula II and their derivatives also have the formula V:

Embedded image Wherein R ¹ , R ² and L have the meanings given above and R
Can be prepared by metallizing to a suitable benzoic acid derivative represented by H or A, and then reacting this product with the corresponding alkenyl halide. An example of a suitable base for this metallation is lithium diisopropylamide.

In the above cross-coupling reaction, the formula V
In, a carboxylic acid or ester derivative in which L is preferably Cl, Br or I is reacted with an organometallic alkenyl compound in the presence of a suitable metal catalyst, in particular one of the catalysts mentioned above. This organometallic alkenyl compound can be produced by in-situ metallization. This reaction is performed similarly to the reaction between compound III and compound IV. This reaction is explained below. However, the compounds of formula II are particularly preferably prepared by the reaction of Heck. This reaction is, for example, J.Org.Ch
em. 46 , 1067 (1981), for example, a compound of the formula V in which L is Br or I is represented by Pd (II)
Salts such as acetate and phosphines such as tri-o-
By reacting with a cyclic or linear alkenyl compound in the presence of tolylphosphine.

The reaction of the reactive carboxylic acid derivative represented by the formula II with guanidine is carried out by a method known per se.
It is preferably carried out in a protic or aprotic polar or non-polar inert organic solvent. Suitable solvents for the reaction of compound III and compound IV are the solvents mentioned below. However, particularly suitable solvents are methanol, tetrahydrofuran, dimethoxyethane, dioxane or mixtures which can be prepared from these solvents and water.
As the reaction temperature, for example, a temperature from 20 ° C. to the boiling point of the solvent is suitable. The reaction time is 5 minutes to 12 hours. It is advantageous to use an acid scavenger for this reaction.
Any type of base that does not interfere with the reaction itself is suitable for this purpose. However, it is particularly suitable to use an inorganic base such as potassium carbonate or an organic base such as triethylamine or pyridine, or else an excess of guanidine.

The compounds of the formula I according to claim 1 can also be prepared by reacting a benzoylguanidine compound of the formula III with a compound of the formula IV. The starting material of the formula III is used in the preparation of amides with correspondingly substituted benzoic acid compounds or reactive acid derivatives which can be derived from these acid compounds, such as acid halides, esters or anhydrides. It can be produced by a simple method by reacting with guanidine under reaction conditions which are known per se and are generally used.
A particularly suitable reaction method is the above-mentioned modification method relating to the reaction of compound II with guanidine. The compounds of formula IV are known per se, and their production is also known. When these compounds are unknown, they can be produced by a method known per se.

The preparation of the compounds of the formula II and also the reaction of the compounds of the formula III with the compounds of the formula IV are carried out in a manner known per se, preferably in a protic or aprotic polar inert organic solvent. To do. In the preparation of compound II, or in the reaction of compound III with compound IV, it is likewise advantageous to carry out these reactions in the presence of a base or with an excess of the base component.
Examples of suitable bases are alkali metal or alkaline earth metal hydroxides, carbonates or alcoholates, or also organic bases, such as triethylamine or pyridine, which are also used in excess.
These can also be used as a solvent at the same time.

Suitable inert solvents are in particular methanol, ethanol, isopropanol, n-butanol or t.
alcohols such as ert-butanol; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane; ethylene glycol monomethyl ether or ethylene glycol monoethyl ether (methyl glycol or ethyl glycol) or ethylene glycol dimethyl ether (diglyme), etc. Glycol ethers; ketones such as acetone or butanone; nitriles such as acetonitrile; nitro compounds such as nitromethane or nitrobenzene; esters such as ethyl acetate; amides such as hexamethyltriamide phosphate; dimethyl sulfoxide (DMSO) Sulfoxides such as; methylene chloride, chloroform, trichlorethylene,
Chlorinated hydrocarbons such as 1,2-dichloroethane or carbon tetrachloride; and hydrocarbons such as benzene, toluene or xylene. Mutual mixtures of these solvents are also suitable.

The Heck reaction is usually at an elevated temperature (1
00-150 ° C) is required. A particularly preferred method involving the reaction of compound III with compound IV is to dissolve the corresponding benzoylguanidine compound and unsaturated hydrocarbon compound together with a Pd (II) catalyst and a triphenylphosphine derivative in dimethylformamide and then add this solution. Consists of heating. If the alkene compound is in gaseous form, this gas is passed through throughout the reaction period. In this case, the reaction is preferably
It can be done in an autoclave. The compounds of the formula I can furthermore be obtained by solvolysis, in particular hydrolysis, or by hydrogenolysis to release them from their functional derivatives.

Suitable starting compounds for this solvolysis or hydrogenolysis are the corresponding protected amino groups and / or hydroxyl groups instead of one or more free amino groups and / or hydroxyl groups. A compound corresponding to formula I but containing an amino protecting group in place of the H atom bonded to the N atom, especially an R'-N group in place of the HN group (wherein R'is A compound having an amino protecting group) and / or a compound having a hydroxyl protecting group in place of the H atom of the hydroxyl group, such as an OR ″ group (wherein R ″ is a hydroxyl protecting group instead of the OH group thereof) Compounds corresponding to Formula I except that

There may be several protected amino and / or hydroxyl groups which may be the same or different in the molecule of the starting compound. If the protective groups present are different from one another, these groups can in some cases be separated selectively.
The term "amino protecting group" is well known and is suitable for protecting (blocking) an amino group from a chemical reaction, but which is readily separated after the desired chemical reaction has taken place at another site in the molecule. Is a term for a group capable of Representative examples of groups of this type include acyl groups, aryl groups (e.g. 2,4-dinitrophenyl (DNP)), aralkoxymethyl groups (e.g., especially unsubstituted or substituted). Benzyloxymethyl (BOM)) or aralkyl groups (eg benzyl, 4-nitrobenzyl or triphenylmethyl).

Since the amino protecting groups are separated after the desired reaction (or series of reactions), there is no particular restriction on their nature and size. However, 1-2 C atoms
Groups having 0, especially 1 to 8, are preferred. In the context of the method of the present invention, the term "acyl group" should be interpreted in its broadest sense. Acyl groups include acyl groups derived from aliphatic, araliphatic, aromatic or heterocyclic carboxylic acids or sulphonic acids, and also especially alkoxycarbonyl groups, aryloxycarbonyl groups, and especially aralkyl groups. Coxycarbonyl groups are included.

Examples of acyl groups of this kind are alkanoyl, such as acetyl, propionyl or butyryl; aralkanoyl, such as phenylacetyl; aroyl, such as benzoyl or toluoyl; aryloxyalkanoyl, such as phenoxyacetyl; alkoxycarbonyl, such as methoxycarbonyl, Ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl (BOC) or 2-iodoethoxycarbonyl; or aralkyloxycarbonyl, such as benzyloxycarbonyl (CBZ), 4-methoxybenzyloxycarbonyl. Or there is 9-fluorenylmethoxycarbonyl (FMOC). Preferred amino protecting groups are BOC, D
NP and BOM, also CBZ, benzyl and acetyl.

The term "hydroxyl protecting group" is also a well known term suitable for protecting a hydroxyl group against a chemical reaction, but after the desired chemical reaction has taken place at another site in the molecule. , Is a term for a group that can be easily separated. Representative groups of this type are the abovementioned unsubstituted or substituted aryl, aralkyl or acyl groups, and also alkyl groups. The hydroxyl protecting groups are separated after the desired chemical reaction or sequence of reactions has taken place, so that the nature and size of these hydroxyl protecting groups is not particularly limited; 1 to 20 C atoms, in particular 1 Groups having from 10 to 10 are preferred. Examples of hydroxyl protecting groups include, among others, ter
There are t-butyl, benzyl, p-nitrobenzoyl, p-toluenesulfonyl and acetyl, with benzyl and acetyl being especially preferred.

The functional derivatives of the compounds of the formula I used as starting compounds are prepared using conventional methods, as described in the publications, for example in the standard academic and patent applications mentioned above, For example, it can be produced by reacting a compound corresponding to formula II and a compound corresponding to formula III, at least one of these compounds having a protecting group in place of the H atom.
Depending on the protecting groups used, the compounds of the formula I can be obtained from their functional derivatives, for example by using strong acids, preferably trifluoroacetic acid or perchloric acid, Alternatively, it can be liberated using other strong inorganic acids such as hydrochloric acid or sulfuric acid, or strong organic carboxylic acids such as trichloroacetic acid, or sulfonic acids such as benzenesulfonic acid or p-toluenesulfonic acid. The reaction can be carried out in the presence of an additional inert solvent, but this is not always necessary.

Suitable inert solvents are preferably organic solvents, for example carboxylic acids such as acetic acid, ethers such as tetrahydrofuran (THF) or dioxane,
Amides such as dimethylformamide (DMF), halogenated hydrocarbons such as methylene chloride, alcohols such as methanol, ethanol or isopropanol and water can also be used.
Mixtures of the solvents mentioned can also be used. Trifluoroacetic acid is preferably used in excess without the use of an additional solvent, and perchloric acid is preferably used in the form of a mixture of acetic acid and 70% perchloric acid in the ratio 9: 1. The reaction temperature suitable for this cleavage reaction is advantageously about 0 to about 50 °; the reaction is preferably carried out at 15 to 30 ° (room temperature).

The BOC groups are preferably 15 to 15%, for example with 40% trifluoroacetic acid in methylene chloride or with about 3-5N HCl in dioxane.
It can be separated at 60 ° and the FMOC groups can be separated at 15-50 ° with a solution of dimethylamine, diethylamine or piperidine in DMF at approximately 5-20%. The DNP group also has, for example, approximately 3-1 of 2-mercaptoethanol in DMF / water.
A 0% solution can be used to separate at 15-30 °.

Protecting groups which can be separated by hydrogenolysis (eg BOM, CBZ or benzyl) are:
For example, in the presence of a catalyst (eg palladium, preferably a precious metal catalyst such as palladium on a support such as charcoal),
It can be separated by treatment with hydrogen. Suitable solvents in this case are the solvents mentioned above, in particular alcohols such as methanol or ethanol or amides such as DMF. This hydrogenolysis is generally carried out at temperatures of about 0-100 ° and pressures of about 1-200 bar, preferably at 20-30 ° at pressures of 1-10 bar. Hydrogenolysis of the CBZ group is well achieved, for example, in methanol at 20-30 ° on 5-10% Pd-C.

The compounds of formula I can also be prepared by converting the corresponding precursor compounds of the compounds of formula I into such compounds by reduction. Thus, for example, by itself corresponding to formula I, but R ³
Compounds having an alkynyl substituent in place of can be converted to compounds of formula I by partial catalytic hydrogenation. Such reduction is preferably hydrogenated using hydrogen gas in the presence of a catalyst, such as Pd, Pt, Lindlar catalyst, and the like.
The compounds of formula I can also be converted into other compounds of formula I by isomerizing the double bond present in the substituent R ³ . This isomerization is preferably carried out under the influence of heat in the presence of a catalyst. Suitable catalysts are, for example, Pt or Pd salts, other transition metal catalysts, or metal carbonates. By way of example, bis (benzonitrile) palladium (II) chloride is particularly suitable. This method is called Durvasula
Tetrahedron Lett. 22 , 2337 (1981).

The base compounds of formula I can also be converted with acids into the corresponding acid addition salts. Acids that form physiologically acceptable salts can be used in this reaction. Thus, inorganic acids such as sulfuric acid, nitric acid, hydrohalic acids such as hydrochloric acid or hydrobromic acid,
Phosphoric acid, such as orthophosphoric acid, or sulfamic acid, and also organic acids, especially aliphatic, cycloaliphatic, aromatic-
Aliphatic, aromatic or heterocyclic monobasic or polybasic carboxylic acids, sulfonic acids or sulfuric acids, such as formic acid, acetic acid, propionic acid, pivalic acid, diethyl acetic acid,
Malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, benzoic acid, salicylic acid, 2- or 3-phenylpropionic acid, citric acid,
Gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methanesulfonic acid, ethanesulfonic acid, ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenemonosulfonic acid, naphthalenedisulfonic acid Alternatively, lauryl sulfate can be used.

The compounds of formula I and their physiologically acceptable salts can be used for the preparation of pharmaceutical preparations, especially by the non-chemical route. These compounds, together with at least one solid, liquid and / or semi-liquid carrier or auxiliary, optionally one or two
Suitable dosage forms can be made by combining one or more other active ingredients. The present invention also relates to formulations, in particular pharmaceutical formulations, which contain at least one of the compounds of the formula I and / or one of its physiologically acceptable salts.

These formulations can be used as medicaments in human or veterinary medicine. Carriers which can be used are suitable for enteral (eg oral), parenteral or topical administration, and also organic or inorganic substances, such as water, vegetable oils, benzyl alcohol, polyethylene glycol, glycerol, which do not react with the novel compounds according to the invention. There are triacetate, gelatin, carbohydrates (eg lactose or starch), magnesium stearate, talc, lanolin and petroleum jelly. Tablets, coated tablets, capsules,
Syrups, juices or drops are used especially for oral administration, suppositories are used for rectal administration, solutions, preferably oily or aqueous solutions and also suspensions, emulsions or implants are used for parenteral administration, and ointments ,
Creams, pastes, lotions, gels, sprays, foams, aerosols, solutions (eg alcohols such as ethanol or isopropanol, acetonitrile, DM
F, dimethylacetamide, 1,2-propanediol or solutions thereof with each other and / or with water) or also powders are used for topical administration. The novel compounds of the present invention can also be lyophilized, and the resulting lyophilizate can be used, for example, in the manufacture of injectable formulations.

Liposomal formulations are also possible and are particularly suitable for topical use. The formulations can be sterilized and / or auxiliary agents such as lubricants, preservatives, stabilizers and / or wetting agents, emulsifiers, salts which influence the osmotic pressure,
Buffering agents, colorants, flavoring agents and / or aroma substances can be included. If desired, these formulations may also contain one or more additional active ingredients such as
It may contain one or more vitamins. The compounds of formula I and their physiologically acceptable salts can be administered to humans or animals, in particular mammals such as monkeys, dogs, cats, rats or mice, for the treatment of the human or animal body. It can be used for therapeutic treatment and for combating diseases, in particular for the treatment and / or prevention of disorders of the cardiovascular system. Therefore, these preparations are useful for the treatment of arrhythmias, especially for the treatment of arrhythmias caused by lack of oxygen, for angina, infarction, ischemia of the nervous system, such as stroke or cerebral edema, or also for the treatment of shock conditions. , And also suitable for prophylactic treatment.

The substances according to the invention also furthermore relate to diseases in which cell proliferation plays a role, for example arteriosclerosis, late complications of diabetes, tumor diseases, fibrosis and organ hyperplasia and hypertrophy, in particular prostate diseases. In addition, it can be used as a therapeutic drug. The substances according to the invention are generally administered in the same manner as known antiarrhythmic agents, for example aprindine, preferably from about 0.01 to 5 m / dosage unit.
g, especially 0.02-0.5 mg. The daily dose is preferably about 0.0001-0.1 mg /
Kg body weight, especially 0.0003-0.01 mg / kg body weight
It is. However, the particular dosage for each particular patient will depend on a very wide variety of factors such as efficacy of the particular compound used, age, weight, general health and sex, diet, time and method of administration, excretion. It depends on the rate, the drug combination and the severity of the particular disease being treated. Oral administration is preferred.

[0043]

EXAMPLES In the following examples, the term "conventional work-up" shall have the following meaning: if necessary, water is added and the mixture is extracted with an organic solvent such as ethyl acetate. The organic phase is separated off, dried over sodium sulphate, filtered then evaporated and the residue is purified by chromatography and / or crystallization.

Example 1 5.6 g of guanidinium chloride and 1.6 of sodium in 40 ml of ethylene glycol dimethyl ether.
The fresh guanidine solution prepared from g was cooled with ice to 2-methyl-4- (1-cyclopenten-3-yl)-in 20 ml ethylene glycol dimethyl ether.
5-methylsulfonyl benzoyl chloride 1.2g
[This compound is methyl 2-methyl-4-bromo-5
-Methyl-sulfonylbenzoate was reacted with cyclopentene in the presence of Pd (II) acetate and tri-o-tolylphosphine and then loaded with LiChroprep RP-18 [Prebar®] ] Stainless Steel Cartridge 2
50-50, 0.1m NaH ₂ as eluent
Separation into two isomers by elution with PO ₄ buffer / acetonitrile 9: 1 with an increasing gradient up to 1: 1 followed by hydrolysis and subsequent conversion to acid chloride with SOCl _2. Obtained by] and the mixture is stirred at room temperature for 2 hours. The reaction mixture was then poured onto ice-water, acidified and washed with ethyl acetate, then the pH of the solution was adjusted to 10
Adjust to Subjected to conventional workup, N-diaminomethylene-2-methyl-4- (1-cyclopentene-3-
Yl) -5-methylsulfonylbenzamide is obtained. The product can be recrystallized from acetonitrile / diethyl ether, mp: 212-214 °.

Similarly, the following compound is obtained by reaction with guanidine: 2-methyl-4- (1-propene-
1-yl) -5-methylsulfonylbenzoyl chloride was reacted to give N-diaminomethylene-2-methyl-
4- (1-propen-1-yl) -5-methylsulfonylbenzamide is obtained, mp: 202-204 °; 2-
Methyl-4-ethenyl-5-methylsulfonylbenzoyl chloride was reacted to give N-diaminomethylene-2.
-Methyl-4-ethenyl-5-methylsulfonylbenzamide is obtained; 2-methyl-4- (1-propen-2-
Yl) -5-methylsulfonylbenzoyl chloride to react with N-diaminomethylene-2-methyl-4-
(1-propen-2-yl) -5-methylsulfonylbenzamide is obtained, melting point: 168 °;

2-Methyl-4- (1-propen-3-yl) -5-methylsulfonylbenzoyl chloride was reacted to give N-diaminomethylene-2-methyl-4-.
Obtaining (1-propen-3-yl) -5-methylsulfonylbenzamide; 2-methyl-4- (1-butene-4)
-Yl) -5-methylsulfonylbenzoyl chloride to react with N-diaminomethylene-2-methyl-4
-(1-Buten-4-yl) -5-methylsulfonylbenzamide is obtained; 2-methyl-4- (2-methyl-1)
-Propen-1-yl) -5-methylsulfonylbenzoyl chloride was reacted to give N-diaminomethylene-
2-Methyl-4- (2-methyl-1-propen-1-yl) -5-methylsulfonylbenzamide is obtained; 2-
Methyl-4- (2-buten-1-yl) -5-methylsulfonylbenzoyl chloride was reacted to give N-diaminomethylene-2-methyl-4- (2-buten-1-yl) -5-methylsulfonyl. Obtain benzamide;

2-Methyl-4- (2-buten-2-yl) -5-methylsulfonylbenzoyl chloride was reacted to give N-diaminomethylene-2-methyl-4-.
(2-buten-2-yl) -5-methylsulfonylbenzamide is obtained; 2-methyl-4- (3-methyl-2-
Butene-2-yl) -5-methylsulfonylbenzoyl chloride is reacted to give N-diaminomethylene-2-
Methyl-4- (3-methyl-2-buten-2-yl)-
5-methylsulfonylbenzamide is obtained; 2-methyl-4- (1-buten-3-yl) -5-methylsulfonylbenzoyl chloride is reacted to give N-diaminomethylene-2-methyl-4- (1-butene. -3-yl)-
Obtaining 5-methylsulfonylbenzamide, melting point: 18
6-188 °; 2-methyl-4- (1-buten-1-yl) -5-methylsulfonylbenzoyl chloride was reacted to give N-diaminomethylene-2-methyl-4-.
Obtain (1-buten-1-yl) -5-methylsulfonylbenzamide;

2-Methyl-4- (1-buten-2-yl) -5-methylsulfonylbenzoyl chloride was reacted to give N-diaminomethylene-2-methyl-4-.
(1-buten-2-yl) -5-methylsulfonylbenzamide is obtained; 2-methyl-4- (1-buten-3-
Yl) -5-methylsulfonylbenzoyl chloride to react with N-diaminomethylene-2-methyl-4-
Obtaining (1-buten-3-yl) -5-methylsulfonylbenzamide; 2-methyl-4- (1-pentene-1
-Yl) -5-methylsulfonylbenzoyl chloride to react with N-diaminomethylene-2-methyl-4
-(1-Penten-1-yl) -5-methylsulfonylbenzamide is obtained; 2-methyl-4- (1-cyclopenten-4-yl) -5-methylsulfonylbenzoyl chloride is reacted to give N-diaminomethylene. -2-
Methyl-4- (1-cyclopenten-4-yl) -5-
Obtaining methylsulfonylbenzamide, melting point: 198
゜;

2-Methyl-4- (2-penten-1-yl) -5-methylsulfonylbenzoyl chloride was reacted to give N-diaminomethylene-2-methyl-4-.
(2-Penten-1-yl) -5-methylsulfonylbenzamide is obtained; 2-methyl-4- (3-pentene-
1-yl) -5-methylsulfonylbenzoyl chloride was reacted to give N-diaminomethylene-2-methyl-
4- (3-Penten-1-yl) -5-methylsulfonylbenzamide is obtained; 2-methyl-4- (1-hexen-1-yl) -5-methylsulfonylbenzoyl chloride is reacted to give N-diamino. Obtain methylene-2-methyl-4- (1-hexen-1-yl) -5-methylsulfonylbenzamide; react with 2-methyl-4- (2-hexen-1-yl) -5-methylsulfonylbenzoyl chloride Let me N-diaminomethylene-2-
Methyl-4- (2-hexen-1-yl) -5-methylsulfonylbenzamide is obtained; 2-methyl-4- (3
-Hexen-1-yl) -5-methylsulfonylbenzoyl chloride was reacted to give N-diaminomethylene-
2-Methyl-4- (3-hexen-1-yl) -5-methylsulfonylbenzamide is obtained.

Example 2 As in Example 1, 1.8 g of 2-ethyl-4- (1-cyclopenten-3-yl) -5-methylsulfonylbenzoyl chloride was reacted with guanidine and subjected to conventional work-up. N-diaminomethylene-2-ethyl-4-
(1-Cyclopenten-3-yl) -5-methylsulfonylbenzamide is obtained. The product can be recrystallized from acetonitrile / diethyl ether.
Similarly, reaction with guanidine gives the following compound:

2-Ethyl-4- (1-propen-1-yl) -5-methylsulfonylbenzoyl chloride was reacted to give N-diaminomethylene-2-ethyl-4-.
(1-propen-1-yl) -5-methylsulfonylbenzamide is obtained; 2-ethyl-4-ethenyl-5-methylsulfonylbenzoyl chloride is reacted to give N
-Diaminomethylene-2-ethyl-4-ethenyl-5-
Methylsulfonylbenzamide is obtained; 2-ethyl-4
Reaction with-(1-propen-2-yl) -5-methylsulfonylbenzoyl chloride to give N-diaminomethylene-2-ethyl-4- (1-propen-2-yl)-
5-methylsulfonylbenzamide is obtained; 2-ethyl-4- (1-propen-3-yl) -5-methylsulfonylbenzoyl chloride is reacted to give N-diaminomethylene-2-ethyl-4- (1-propene. -3-yl) -5-methylsulfonylbenzamide is obtained;

2-Ethyl-4- (1-buten-4-yl) -5-methylsulfonylbenzoyl chloride was reacted to give N-diaminomethylene-2-ethyl-4-.
Obtaining (1-buten-4-yl) -5-methylsulfonylbenzamide; 2-ethyl-4- (2-ethyl-1-)
Propene-1-yl) -5-methylsulfonylbenzoyl chloride is reacted to give N-diaminomethylene-2.
-Ethyl-4- (2-ethyl-1-propen-1-yl) -5-methylsulfonylbenzamide is obtained; 2-
N-diaminomethylene-2-ethyl-4- (1-buten-1-yl) -5-methylsulfonyl was reacted with ethyl-4- (1-buten-1-yl) -5-methylsulfonylbenzoyl chloride. Obtain benzamide; 2-
Ethyl-4- (2-buten-2-yl) -5-methylsulfonylbenzoyl chloride was reacted to give N-diaminomethylene-2-ethyl-4- (2-buten-2-yl) -5-methylsulfonyl. Obtain benzamide;

2-Ethyl-4- (3-methyl-2-buten-2-yl) -5-methylsulfonylbenzoyl chloride was reacted to give N-diaminomethylene-2-ethyl-4- (3-methyl-). 2-buten-2-yl) -5-
Methylsulfonylbenzamide is obtained; 2-ethyl-4
N-diaminomethylene-2-ethyl-4- (1-buten-3-yl) -5- is reacted with-(1-buten-3-yl) -5-methylsulfonylbenzoyl chloride.
Methylsulfonylbenzamide is obtained; 2-ethyl-4
N-diaminomethylene-2-ethyl-4- (1-buten-1-yl) -5-reacted with-(1-buten-1-yl) -5-methylsulfonylbenzoyl chloride.
Methylsulfonylbenzamide is obtained; 2-ethyl-4
N-diaminomethylene-2-ethyl-4- (1-buten-2-yl) -5- is reacted with-(1-buten-2-yl) -5-methylsulfonylbenzoyl chloride.
Obtain methylsulfonylbenzamide;

2-Ethyl-4- (1-buten-3-yl) -5-methylsulfonylbenzoyl chloride was reacted to give N-diaminomethylene-2-ethyl-4-.
Obtaining (1-buten-3-yl) -5-methylsulfonylbenzamide; 2-ethyl-4- (1-pentene-1
-Yl) -5-methylsulfonylbenzoyl chloride was reacted to give N-diaminomethylene-2-ethyl-4.
-(1-Penten-1-yl) -5-methylsulfonylbenzamide is obtained; 2-ethyl-4- (2-penten-1-yl) -5-methylsulfonylbenzoyl chloride is reacted to give N-diaminomethylene. 2-ethyl-4- (2-penten-1-yl) -5-methylsulfonylbenzamide is obtained; reacted with 2-ethyl-4- (3-penten-1-yl) -5-methylsulfonylbenzoyl chloride To give N-diaminomethylene-2-ethyl-4- (3-penten-1-yl) -5-methylsulfonylbenzamide;

2-Ethyl-4- (1-hexen-1-yl) -5-methylsulfonylbenzoyl chloride was reacted to give N-diaminomethylene-2-ethyl-4-.
(1-Hexen-1-yl) -5-methylsulfonylbenzamide is obtained; 2-ethyl-4- (2-hexene-
1-yl) -5-methylsulfonylbenzoyl chloride was reacted to give N-diaminomethylene-2-ethyl-
4- (2-Hexen-1-yl) -5-methylsulfonylbenzamide is obtained; 2-ethyl-4- (3-hexen-1-yl) -5-methylsulfonylbenzoyl chloride is reacted to give N-diamino. Methylene-2-ethyl-4- (3-hexen-1-yl) -5-methylsulfonylbenzamide is obtained.

Example 3 80 ml of cyclopentene was added to N-diaminomethylene-2.
-Methyl-4-bromo-5-methylsulfonylbenzamide 32 g [This compound is 2-methyl-4-bromo-
Obtained by reacting 5-methylsulfonylbenzoyl chloride with guanidine], to a suspension of 40 ml triethylamine, 0.4 g Pd (II) acetate, 0.8 g tri-o-tolylphosphine and 80 ml dimethylformamide (DMF). Add and then heat the reaction mixture at 100-110 ° for 8 hours. The solvent is then removed, 300 ml of water are added, the mixture is acidified and then washed several times with ethyl acetate, then the pH of the solution is adjusted to 10.

Subjected to conventional finishing, N-diaminomethylene-2-methyl-4- (1-cyclopentene-3).
-Yl) -5-methylsulfonylbenzamide (88
%) And N-diaminomethylene-2-methyl-4- (1-
An isomer mixture with cyclopenten-4-yl) -5-methylsulfonylbenzamide (12%) is obtained. Preber (registered trade name) packed with Licroprep RP-18 to separate this isomer
Introduced into stainless steel cartridge 250-50, 0.
Elute with 1m NaH ₂ PO ₄ buffer / acetonitrile 9: 1 with increasing gradient up to 1: 1. Isomer 1: N-diaminomethylene-2-methyl-4-
(1-Cyclopenten-3-yl) -5-methylsulfonylbenzamide, melting point: 212-214 ° isomer 2: N-diaminomethylene-2-methyl-4-
(1-Cyclopenten-4-yl) -5-methylsulfonylbenzamide.

Example 4 700 mg of N-diaminomethylene-2-methyl-4- (1-cyclopenten-3-yl) -5-methylsulfonylbenzamide [This compound can be prepared according to Example 1; melting point: 212- 214 °] with acetone 2
Dissolve in 0 ml, then 6.1 ml methanesulfonic acid
Is added with stirring. Filtered, lyophilized, N
-Diaminomethylene-2-methyl-4- (1-cyclopenten-3-yl) -5-methylsulfonylbenzamide, methanesulfonate is obtained, melting point: 202-204.
゜. Similarly, the following methanesulfonates are obtained from the free base:

N-diaminomethylene-4- (1-cyclopenten-3-yl) -5-methylsulfonylbenzamide, methanesulfonate, melting point: 225 °; N-diaminomethylene-2-methyl-4- (1- Cyclopenten-1-yl) -5-methylsulfonylbenzamide, methanesulfonate, melting point: 218-220 °; N-diaminomethylene-2-methyl-4- (1-propen-1-
Yl) -5-methylsulfonylbenzamide, methanesulfonate, melting point: 207-209 °; N-diaminomethylene-2-methyl-4- (1-cyclopentenyl-4)
-Yl) -5-methylsulfonylbenzamide, methanesulfonate, melting point: 186 [deg.]; N-diaminomethylene-2-methyl-4- (1-buten-3-yl) -5-methylsulfonylbenzamide, methanesulfonic acid Salt, melting point: 122 °; N-diaminomethylene-4- (1-propenyl-1-yl) -5-methylsulfonylbenzamide, methanesulfonate, melting point: 250-252 °; N
-Diaminomethylene-2-methyl-4- (1-propenyl-2-yl) -5-methylsulfonylbenzamide,
Methanesulfonate, melting point: 172 °.

Example 5 In the same manner as in Example 1, 3-methylsulfonyl-4- (1-
2.2 g of cyclopenten-3-yl) -benzoyl chloride are reacted with guanidine and then subjected to conventional work-up to give N-diaminomethylene-3-methylsulfonyl-4- (1-cyclopenten-3-yl) benzamide. obtain. This product can be recrystallized from acetonitrile / diethyl ether, mp: 188-
190 °. Similarly, reaction with guanidine gives the following compound:

Reaction with 3-methylsulfonyl-4- (1-propen-1-yl) benzoyl chloride to give N
-Diaminomethylene-3-methylsulfonyl-4- (1
-Propen-1-yl) benzamide is obtained, melting point: 2
23-225 °; React with 3-methylsulfonyl-4-ethenylbenzoyl chloride to give N-diaminomethylene-3-methylsulfonyl-4-ethenylbenzamide; 3-methylsulfonyl-4- (1-propene -2-yl) benzoyl chloride to react with N-
Diaminomethylene-3-methylsulfonyl-4- (1-
Propene-2-yl) benzamide is obtained; 3-methylsulfonyl-4- (1-propen-3-yl) benzoyl chloride is reacted to give N-diaminomethylene-3.
-Methylsulfonyl-4- (1-propen-3-yl)
Obtain benzamide;

3-Methylsulfonyl-4- (1-buten-4-yl) benzoyl chloride was reacted to give N-
Diaminomethylene-3-methylsulfonyl-4- (1-
Butene-4-yl) benzamide is obtained; 3-methylsulfonyl-4- (3-methylsulfonyl-1-propen-1-yl) benzoyl chloride is reacted to give N-
Diaminomethylene-3-methylsulfonyl-4- (3-
Methylsulfonyl-1-propen-1-yl) benzamide is obtained; 3-methylsulfonyl-4- (2-buten-1-yl) benzoyl chloride is reacted to give N-
Diaminomethylene-3-methylsulfonyl-4- (2-
Butene-1-yl) benzamide is obtained; 3-methylsulfonyl-4- (2-buten-2-yl) benzoyl chloride is reacted to give N-diaminomethylene-3-methylsulfonyl-4- (2-butene- 2-yl) benzamide is obtained;

N-diaminomethylene-3-methylsulfonyl-4- (3-methyl-2-butene) was reacted with 3-methylsulfonyl-4- (3-methyl-2-buten-2-yl) benzoyl chloride. 2-yl) benzamide is obtained; 3-methylsulfonyl-4- (1-buten-3-yl) benzoyl chloride is reacted to give N-
Diaminomethylene-3-methylsulfonyl-4- (1-
Butene-3-yl) benzamide is obtained; 3-methylsulfonyl-4- (1-buten-1-yl) benzoyl chloride is reacted to give N-diaminomethylene-3-methylsulfonyl-4- (1-butene- 1-yl) benzamide is obtained; 3-methylsulfonyl-4- (1-buten-2-yl) benzoyl chloride is reacted to give N.
-Diaminomethylene-3-methylsulfonyl-4- (1
-Buten-2-yl) benzamide is obtained;

3-Methylsulfonyl-4- (1-buten-3-yl) benzoyl chloride was reacted to give N-
Diaminomethylene-3-methylsulfonyl-4- (1-
Butene-3-yl) benzamide is obtained; 3-methylsulfonyl-4- (1-penten-1-yl) benzoyl chloride is reacted to give N-diaminomethylene-3-.
Methylsulfonyl-4- (1-penten-1-yl) benzamide is obtained; 3-methylsulfonyl-4- (2-
Penten-1-yl) benzoyl chloride was reacted to give N-diaminomethylene-3-methylsulfonyl-4.
-(2-Penten-1-yl) benzamide is obtained; 3
-Methylsulfonyl-4- (3-penten-1-yl)
Reaction with benzoyl chloride gives N-diaminomethylene-3-methylsulfonyl-4- (3-pentene-1
-Yl) to obtain benzamide;

Reaction with 3-methylsulfonyl-4- (1-hexen-1-yl) benzoyl chloride to give N
-Diaminomethylene-3-methylsulfonyl-4- (1
-Hexen-1-yl) benzamide is obtained; 3-methylsulfonyl-4- (2-hexen-1-yl) benzoyl chloride is reacted to give N-diaminomethylene-
3-Methylsulfonyl-4- (2-hexen-1-yl) benzamide is obtained; 3-methylsulfonyl-4-
Reaction with (3-hexen-1-yl) benzoyl chloride gives N-diaminomethylene-3-methylsulfonyl-4- (3-hexen-1-yl) benzamide.

Example 6 N-diaminomethylene-2-methyl-4-ethynyl-5
-Methylsulfonylbenzamide (melting point: 223-22
6 °) 6.0 g [This compound is methyl 2-methyl-
4-Bromo-5-methylsulfonylbenzoate was added to Li
Reacted with acetylide to give methyl 2-methyl-4-
Ethynyl-5-methylsulphonylbenzoate is produced and then reacted with guanidine] is dissolved in 300 ml DMF and then Pd-C
In the presence of 450 mg of aCO ₃ (Lindler catalyst),
Hydrogenate in flowing hydrogen (p = 1 bar) for 15 minutes.
Subjected to conventional finishing treatment, N-diaminomethylene-2-
Methyl-4-ethenyl-5-methylsulfonylbenzamide is obtained.

Similarly, H _{2 in} the presence of Lindlar's catalyst
Hydrogenation with gives the following compound: N
-Diaminomethylene-2-methyl-4- (1-propyn-1-yl) -5-methylsulfonylbenzamide to N-diaminomethylene-2-methyl-4- (1-propen-1-yl) -5-methyl A sulfonylbenzamide is obtained; N-diaminomethylene-2-methyl-4-
(1-Propin-3-yl) -5-methylsulfonylbenzamide to N-diaminomethylene-2-methyl-4
-(1-Propen-3-yl) -5-methylsulfonylbenzamide is obtained; N-diaminomethylene-2-
N-diaminomethylene-2-ethyl-4-ethenyl-5-methylsulfonylbenzamide is obtained from ethyl-4-ethynyl-5-methylsulfonylbenzamide;

N-diaminomethylene-2-ethyl-4-
From (1-propyn-3-yl) -5-methylsulfonylbenzamide to N-diaminomethylene-2-ethyl-4
-(1-Propen-3-yl) -5-methylsulfonylbenzamide is obtained; N-diaminomethylene-2-
Ethyl-4- (1-propyn-1-yl) -5-methylsulfonylbenzamide to N-diaminomethylene-2
-Ethyl-4- (1-propen-1-yl) -5-methylsulfonylbenzamide is obtained;

Example 7 To a solution of 1 g of N-diaminomethylene-2-methyl-4- (1-cyclopenten-3-yl) -5-methylsulfonylbenzamide [this compound is obtained according to Example 1] in 20 ml of toluene. , Bis (benzonitrile) -P
80 g of d (II) chloride was added and the mixture was added to 2
Bring to boiling reflux for an hour. After filtration, removal of the solvent and customary work-up, an isomer mixture consisting of three isomers is obtained. After pre-purifying the isomer mixture by chromatography (silica gel / ethyl acetate-methanol 9: 1), the mixture was lyroprep RP-
Introduced onto a Prever® stainless steel cartridge 250-50 filled with 18 and eluting with a 9: 1 ratio of 0.1m NaH ₂ PO ₄ buffer / acetonitrile in an increasing gradient to a 1: 1 ratio. To separate the isomers. This gives the following isomers:

Isomer 1: N-diaminomethylene-2-methyl-4-
(1-Cyclopenten-3-yl) -5-methylsulfonylbenzamide, melting point: 184-186 ° (14
%); Isomer 2: N-diaminomethylene-2-methyl-4-
(1-Cyclopenten-1-yl) -5-methylsulfonylbenzamide, melting point: 138-140 ° (42
%); Isomer 3: N-diaminomethylene-2-methyl-4-
(1-Cyclopenten-4-yl) -5-methylsulfonylbenzamide (44%).

Example 8 As in Example 7, N-diaminomethylene-2-ethyl-4
3.1 g of-(1-cyclopenten-3-yl) -5-methylsulphonylbenzamide [this compound is obtained according to example 2] are added to bis (benzonitrile) -Pd (I
I) Isomerization in the presence of chloride to give the following isomer: Isomer 1: N-diaminomethylene-2-ethyl-4-
(1-Cyclopenten-3-yl) -5-methylsulfonylbenzamide; Isomer 2: N-diaminomethylene-2-ethyl-4-
(1-Cyclopenten-1-yl) -5-methylsulfonylbenzamide; Isomer 3: N-diaminomethylene-2-ethyl-4-
(1-Cyclopenten-4-yl) -5-methylsulfonylbenzamide.

Example 9 As in Example 1, 2-methyl-4- (1-cyclopenten-3-yl) -5-nitrobenzoyl chloride 1.8
After reacting g with guanidine and after conventional work-up,
N-diaminomethylene-2-methyl-4- (1-cyclopenten-3-yl) -5-nitrobenzamide is obtained. The product can be recrystallized from acetonitrile / diethyl ether. Similarly, reaction with guanidine gives the following compound:

2-methyl-4- (1-propen-1-yl) -5-nitrobenzoyl chloride was reacted,
N-diaminomethylene-2-methyl-4- (1-propen-1-yl) -5-nitrobenzamide is obtained; 2-
Methyl-4-ethenyl-5-nitrobenzoyl chloride was reacted to give N-diaminomethylene-2-methyl-
4-Ethenyl-5-nitrobenzamide is obtained; 2-methyl-4- (1-propen-2-yl) -5-nitrobenzoyl chloride is reacted to give N-diaminomethylene-2-methyl-4- (1. -Propen-2-yl) -5
-Nitrobenzamide is obtained; 2-methyl-4- (1-
Reaction with propen-3-yl) -5-nitrobenzoyl chloride to give N-diaminomethylene-2-methyl-
Obtain 4- (1-propen-3-yl) -5-nitrobenzamide;

2-methyl-4- (1-buten-4-yl) -5-nitrobenzoyl chloride was reacted,
N-diaminomethylene-2-methyl-4- (1-buten-4-yl) -5-nitrobenzamide is obtained; 2-methyl-4- (2-methyl-1-propen-1-yl)-
N-diaminomethylene-2-methyl-4- (2-methyl-1-) was reacted with 5-nitrobenzoyl chloride.
Propene-1-yl) -5-nitrobenzamide is obtained; 2-methyl-4- (2-buten-1-yl) -5-
Reacting nitrobenzoyl chloride to give N-diaminomethylene-2-methyl-4- (2-buten-1-yl) -5-nitrobenzamide;

2-methyl-4- (2-buten-2-yl) -5-nitrobenzoyl chloride was reacted,
N-diaminomethylene-2-methyl-4- (2-buten-2-yl) -5-nitrobenzamide is obtained; 2-methyl-4- (3-methyl-2-buten-2-yl) -5.
-Reacted with nitrobenzoyl chloride to give N-diaminomethylene-2-methyl-4- (3-methyl-2-buten-2-yl) -5-nitrobenzamide; 2
-Methyl-4- (1-buten-3-yl) -5-nitrobenzoyl chloride was reacted to give N-diaminomethylene-2-methyl-4- (1-buten-3-yl) -5.
-Nitrobenzamide is obtained; 2-methyl-4- (1-
Buten-1-yl) -5-nitrobenzoyl chloride is reacted to give N-diaminomethylene-2-methyl-4.
-(1-buten-1-yl) -5-nitrobenzamide is obtained;

2-methyl-4- (1-buten-2-yl) -5-nitrobenzoyl chloride was reacted,
N-diaminomethylene-2-methyl-4- (1-buten-2-yl) -5-nitrobenzamide is obtained; 2-methyl-4- (1-buten-3-yl) -5-nitrobenzoyl chloride is obtained. Reaction to give N-diaminomethylene-2-methyl-4- (1-buten-3-yl) -5-nitrobenzamide; 2-methyl-4- (1-penten-1-yl) -5- Reaction with nitrobenzoyl chloride to give N-diaminomethylene-2-methyl-4-
(1-Penten-1-yl) -5-nitrobenzamide is obtained; 2-methyl-4- (2-penten-1-yl)
N- by reacting with 5-nitrobenzoyl chloride
Diaminomethylene-2-methyl-4- (2-pentene-
1-yl) -5-nitrobenzamide is obtained;

2-methyl-4- (3-penten-1-yl) -5-nitrobenzoyl chloride was reacted,
N-diaminomethylene-2-methyl-4- (3-penten-1-yl) -5-nitrobenzamide is obtained; 2-
Methyl-4- (1-hexen-1-yl) -5-nitrobenzoyl chloride was reacted to give N-diaminomethylene-2-methyl-4- (1-hexen-1-yl)-.
5-nitrobenzamide is obtained; 2-methyl-4- (2
-Hexen-1-yl) -5-nitrobenzoyl chloride is reacted to give N-diaminomethylene-2-methyl-4- (2-hexen-1-yl) -5-nitrobenzamide; 2-methyl- 4- (3-hexene-1-
Yl) -5-nitrobenzoyl chloride is reacted to give N-diaminomethylene-2-methyl-4- (3-hexen-1-yl) -5-nitrobenzamide.

Example 10 As in Example 1, 1.8 g of 2-methyl-4- (1-cyclopenten-3-yl) -5-trifluoromethylbenzoyl chloride are reacted with guanidine and, after conventional work-up, N-diaminomethylene-2-methyl-4-
(1-Cyclopenten-3-yl) -5-trifluoromethylbenzamide is obtained. The product can be recrystallized from acetonitrile / diethyl ether. Similarly, reaction with guanidine gives the following compound:

2-Methyl-4- (1-propen-1-yl) -5-trifluoromethylbenzoyl chloride was reacted to give N-diaminomethylene-2-methyl-4-.
(1-propen-1-yl) -5-trifluoromethylbenzamide is obtained; 2-methyl-4-ethenyl-5-
Reaction with trifluoromethylbenzoyl chloride gives N-diaminomethylene-2-methyl-4-ethenyl-5-trifluoromethylbenzamide; 2-methyl-4- (1-propen-2-yl) -5- Reaction with trifluoromethylbenzoyl chloride gives N-diaminomethylene-2-methyl-4- (1-propene-2
-Yl) -5-trifluoromethylbenzamide is obtained; 2-methyl-4- (1-propen-3-yl) -5
-Reacting with trifluoromethylbenzoyl chloride to give N-diaminomethylene-2-methyl-4- (1-propen-3-yl) -5-trifluoromethylbenzamide;

2-Methyl-4- (1-buten-4-yl) -5-trifluoromethylbenzoyl chloride was reacted to give N-diaminomethylene-2-methyl-4-.
(1-buten-4-yl) -5-trifluoromethylbenzamide is obtained; 2-methyl-4- (2-methyl-1)
-Propen-1-yl) -5-trifluoromethylbenzoyl chloride was reacted to give N-diaminomethylene-2-methyl-4- (2-methyl-1-propen-1-
Yl) -5-trifluoromethylbenzamide;
2-Methyl-4- (2-buten-1-yl) -5-trifluoromethylbenzoyl chloride was reacted to give N
-Diaminomethylene-2-methyl-4- (2-butene-
1-yl) -5-trifluoromethylbenzamide is obtained; 2-methyl-4- (2-buten-2-yl) -5-
Reacting trifluoromethylbenzoyl chloride to give N-diaminomethylene-2-methyl-4- (2-buten-2-yl) -5-trifluoromethylbenzamide;

2-Methyl-4- (3-methyl-2-buten-2-yl) -5-trifluoromethylbenzoyl chloride was reacted to give N-diaminomethylene-2-methyl-4- (3-methyl). -2-buten-2-yl) -5
-Trifluoromethylbenzamide is obtained; 2-methyl-4- (1-buten-3-yl) -5-trifluoromethylbenzoyl chloride is reacted to give N-diaminomethylene-2-methyl-4- (1- Buten-3-yl)
-5-trifluoromethylbenzamide is obtained; 2-methyl-4- (1-buten-1-yl) -5-trifluoromethylbenzoyl chloride is reacted to give N-diaminomethylene-2-methyl-4- (. 1-buten-1-yl) -5-trifluoromethylbenzamide is obtained; 2
-Methyl-4- (1-buten-2-yl) -5-trifluoromethylbenzoyl chloride was reacted to give N-
Diaminomethylene-2-methyl-4- (1-butene-2
-Yl) -5-trifluoromethylbenzamide is obtained;

2-Methyl-4- (1-buten-3-yl) -5-trifluoromethylbenzoyl chloride was reacted to give N-diaminomethylene-2-methyl-4-.
Obtaining (1-buten-3-yl) -5-trifluoromethylbenzamide; 2-methyl-4- (1-pentene-
1-yl) -5-trifluoromethylbenzoyl chloride is reacted to give N-diaminomethylene-2-methyl-4- (1-penten-1-yl) -5-trifluoromethylbenzamide; 2-methyl -4- (2-Penten-1-yl) -5-trifluoromethylbenzoyl chloride was reacted to give N-diaminomethylene-2.
-Methyl-4- (2-penten-1-yl) -5-trifluoromethylbenzamide is obtained; 2-methyl-4-
(3-Penten-1-yl) -5-trifluoromethylbenzoyl chloride was reacted to give N-diaminomethylene-2-methyl-4- (3-penten-1-yl)-
Obtains 5-trifluoromethylbenzamide;

2-Methyl-4- (1-hexen-1-yl) -5-trifluoromethylbenzoyl chloride was reacted to give N-diaminomethylene-2-methyl-4-.
(1-Hexen-1-yl) -5-trifluoromethylbenzamide is obtained; 2-methyl-4- (2-hexen-1-yl) -5-trifluoromethylbenzoyl chloride is reacted to give N-diamino. Methylene-2-methyl-4- (2-hexen-1-yl) -5-trifluoromethylbenzamide is obtained; 2-methyl-4- (3-
Hexen-1-yl) -5-trifluoromethylbenzoyl chloride is reacted to give N-diaminomethylene-
2-Methyl-4- (3-hexen-1-yl) -5-trifluoromethylbenzamide is obtained.

Example 11 As in Example 1, 1.8 g of 2-methyl-4- (1-cyclohexen-3-yl) -5-methylsulfonylbenzoyl chloride are reacted with guanidine and, after conventional work-up, N 2 -Diaminomethylene-2-methyl-4-
(1-Cyclohexen-3-yl) -5-methylsulfonylbenzamide is obtained. The product can be recrystallized from acetonitrile / diethyl ether.
Similarly, reaction with guanidine gives the following compound:

2-methyl-4- (1-cyclohexene-
3-yl) -5-nitrobenzoyl chloride was reacted to give N-diaminomethylene-2-methyl-4- (1-
Cyclohexen-3-yl) -5-nitrobenzamide is obtained; 2-methyl-4- (1-cyclohexene-3-
Yl) -5-trifluorobenzoyl chloride to react with N-diaminomethylene-2-methyl-4- (1
-Cyclohexen-3-yl) -5-trifluorobenzamide is obtained; 2-methyl-4- (1-cyclohexen-3-yl) -5-nitrobenzoyl chloride is reacted to give N-diaminomethylene-2-methyl. -4-
(1-Cyclohexen-3-yl) -5-nitrobenzamide is obtained.

Example 12 As in Example 7, N-diaminomethylene-2-methyl-4
2.3 g of-(1-cyclohexen-3-yl) -5-methylsulfonylbenzamide [this compound is obtained according to Example 11] are added to bis (benzonitrile) -Pd (I
I) Isomerization in the presence of chloride to give the following isomer: Isomer 1: N-diaminomethylene-2-methyl-4-
(1-Cyclohexen-3-yl) -5-methylsulfonylbenzamide; Isomer 2: N-diaminomethylene-2-methyl-4-
(1-Cyclohexen-1-yl) -5-methylsulfonylbenzamide; Isomer 3: N-diaminomethylene-2-methyl-4-
(1-Cyclohexen-4-yl) -5-methylsulfonylbenzamide.

The following examples relate to pharmaceutical formulations. Example A: Injection vial p of a solution of 100 g of the active compound of formula I and 5 g of disodium hydrogen phosphate in 3 l of double distilled water.
H is adjusted to pH 6.5 with 2N hydrochloric acid, sterile filtered, filled into injection vials, then lyophilized under sterile conditions and the vials are sealed under sterile conditions. Each injection vial contains 5 mg of active compound. Example B: Suppository 20 g active compound of formula I and soybean lecithin 10
A mixture with 0 g and 1400 g of cocoa butter is melted, this mixture is poured into a mold and then allowed to cool. Each suppository contains 20 mg of active compound.

Example C: Solution 1 g of the active compound of the formula I, 9.38 g of NaH ₂ PO ₄ .2H ₂ O, Na ₂ H in 940 ml of double distilled water.
A solution of 28.48 g PO ₄ .12H ₂ O and 0.1 g benzalkonium chloride is prepared. P of this solution
The H is adjusted to 6.8, the total volume of this solution is brought to 1 liter and then sterilized by irradiation. This solution can be used in the form of eye drops. Example D: Ointment 500 mg of the active compound of the formula I are mixed under aseptic conditions with 99.5 g of petroleum jelly.

Example E: Tablets A mixture of 1 kg of the active compound of the formula I, 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate is compressed in the customary manner to give each tablet. Forms a tablet containing 10 mg of active compound. Example F: Coated tablets Tablets are pressed in the same manner as in Example E and then coated in a conventional manner with a coating consisting of sucrose, potato starch, talc, tragacanth and colorant.

Example G: Capsules Hard gelatin capsules are loaded with 2 kg of the active compound of formula I in a conventional manner to give capsules, each capsule containing 20 mg of active compound. Example H: Ampoule A solution of 1 kg of the active compound of formula I in 60 liters of double-distilled water is subjected to sterile filtration, filled into ampoules, freeze-dried under sterile conditions and then sealed under sterile conditions. . Each ampoule contains 10 mg of active compound.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification number Internal reference number FI Technical indication location A61K 31/165 ABX A61K 31/165 ABX ACD ACD ACS ACS ADP ADP ADU ADU AED AED AED 49/00 49 / 00 Z C07C 277/08 9451-4H C07C 277/08 (71) Applicant 591032596 Frankfurter Str. 250, D-64293 Darmstadt, Federal Republish of Germany (72) Inventor Rolf Gerecke Germany Day-64293 Darmstadt Frankfurter Strasse 250 (72) Inventor Manfred Baumgart Federal Republic of Germany Day-64293 Darmstadt Frankfurther Straße 250 (72) Inventor Klaus-Otto Mink Germany Day-64293 Darmstadt Frankfurther Straße 250 (72) Inventor Norbert Bayer Germany Day-64293 Darmstadt Frankfurter Strasse 250

Claims (8)

[Claims] 1. An alkenyl-benzoylguanidine derivative represented by the following formula I and a physiologically acceptable salt thereof: embedded image In the formula, R ¹ and R ² are each independently H, Ha
1, A, CN, NO ₂ , CF ₃ , CH ₂ F, CHF ₂ , C ₂
F _5, a CH ₂ CF ₃ or SO _n -R ^4, R ^{3 is, -CR 5 = CR 6 R 7} , -C (R 6 R 5) -CR 7 =
CR ⁹ R ⁸ or ^{-C (R 6 R 5) -C} (R 7 R 8) -CR 9
═CR ¹⁰ R ¹¹ or cycloalkenyl having 3 to 7 C atoms or cycloalkenylalkyl having 4 to 8 C atoms, R ⁴ is A or Ph, R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ are each, independently of one another, H or A, A is alkyl having 1 to 6 C atoms, Hal is F, Cl, Br or I, Ph is phenyl and this group is unsubstituted or has 1, 2 or 3 substituents A, OA, N
R ⁴ R ^5, F, has to Cl, Br, I or CF _3, and n is 1 or 2. 2. (a) N-diaminomethylene-2-methyl-4- (1-) according to claim 1.
Cyclopenten-3-yl) -5-methylsulfonylbenzamide; (b) N-diaminomethylene-2-methyl-4- (1-
(Pen-1-yl) -5-methylsulfonylbenzamide; (c) N-diaminomethylene-2-ethenyl-5-methylsulfonylbenzamide; (d) N-diaminomethylene-2-methyl-4- (1-
Cyclopenten-1-yl) -5-methylsulfonylbenzamide; (e) N-diaminomethylene-2-methyl-4- (1-
(F) N-Diaminomethylene-2-methyl-4- (1-)-propen-3-yl) -5-methylsulfonylbenzamide
Cyclohexen-3-yl) -5-methylsulfonylbenzamide; and physiologically acceptable salts thereof. 3. A process for preparing an alkenyl-benzoylguanidine derivative of formula I as defined in claim 1 and salts thereof, which comprises the formula II: Wherein R ¹ , R ² and R ³ have the meanings given above and Q is Cl, Br, OA, O-CO-A, O-CO-P.
h or OH, or another reactively esterified OH group, or Q is a leaving group that can be easily nucleophilically substituted. With guanidine, or with formula III: Wherein R ¹ and R ² have the meanings given above, and L is
F, Cl, Br or I, represented by benzoylguanidine compound in, if the transition metal catalyst and optionally, in the presence of an activating agent, wherein IV: in R ³ -H IV formula, R ³ is Reacting with an unsaturated hydrocarbon compound of the above meaning, or corresponding to formula I, but with 1 instead of one or more hydrogen atoms
One or more reducible groups such as alkynyl groups, and / or one or more additional C-
A compound having a C bond and / or a C—N bond,
Treated with a reducing agent, or corresponding to formula I, part 1
A compound having one or more solvolytic groups instead of one or more hydrogen atoms is treated with a solvolytic agent, or the group R ³ is isomerized, or a transition metal catalyst and By the rearrangement of the double bond under the action of (or) a metal carbonyl, it is converted to another group R ³ and / or the resulting base of formula I is treated with an acid to give one of its salts. A method for manufacturing, characterized by converting to seeds. 4. A method for producing a pharmaceutical preparation, which comprises:
A compound of formula I according to claim 1 and / or one of its physiologically acceptable salts, together with at least one solid, liquid or semi-liquid carrier or auxiliary, in suitable dosage forms. A manufacturing method characterized by: 5. A pharmaceutical preparation comprising at least one compound of the general formula I according to claim 1 and / or one of its physiologically acceptable salts. 6. Use of a compound of formula I according to claim 1 or a physiologically acceptable salt thereof for the manufacture of a medicament. 7. Use of a compound of formula I according to claim 1 or a physiologically acceptable salt thereof in combating disease. 8. Use of a compound of formula I according to claim 1 for the manufacture of a medicament in the treatment of arrhythmias, angina or infarction and also in the prophylactic treatment of said diseases.